The complement system includes a group of some thirty (30) proteins that are recognized to be an important part of the immune response. The system can be activated by a classical (usually antibody-dependent) or alternative (usually antibody-dependent) pathway. Activation via either pathway leads to the generation of an enzyme called C5 convertase. The convertase helps form a protein called C5b that, among other functions, initiates what is often referred to as the terminal complement pathway. A goal of this pathway is to form a membrane attack complex (MAC) within the membrane of an invading pathogen, thereby causing lysis. The MAC is generally formed by the sequential assembly of complement proteins C6, C7, C8 and (C9)n along with C5b. See generally Walport, M. J. 2001. N. Engl. J. Med. 344: 1058-1066; and 1140-1144.
There are reports of natural and synthetic inhibitors of the complement system. These include certain small molecules, proteins, antibodies, flavanoids, and polysaccharides, for example. See S. Bureeva et al. (2005) Drug Discovery Today 10: 1535.
Neuronal degeneration is a hallmark of many acute and chronic neuropathies. One mode of axonal degeneration, termed Wallerian Degeneration (WD) is a highly destructive process in which the part of an axon distal to an injury dies. Initial abnormities can be seen as early as several hours after injury with more visible WB apparent a day or two later (Ballin R H and Thomas P K (1969) Acta Neuropathol (Berl) 14: 237. For instance, myelin sheaths collapse and become engulfed by scavenging cells (Leonhard et al. (2002) Eur. J. Neurosci. 16: 1654). These processes are associated with eventual nerve repair and regeneration. There are reports that certain complement components mediate the myelin phagocytosis (Dailey et al. (2002) J. Neurosci 18: 6713; and Liu (1999) J. Peripher. Nerv. Syst. 4: 123). Although there is some uncertainty about which complement components are needed to mediate these processes, MAC formation has been reported to essential for rapid WD (Ramaglia, V. et al. (2007) J. Neurosci. 27: 7663).
A variety of nucleic acid antagonists are known. For example, various antisense oligomers have been shown to be useful for several therapeutic, diagnostic, and research applications (see e.g, Cheson, B D (2007) Ther Clin Risk Manag. 3(5):855 (discussing, for instance, favorable clinical trial data for oblimersen). Short interfering RNA (siRNA), a type of RNA antagonist, has been proposed to be a useful therapeutic and research tool (McManus and Sharp, (2002) Nature Reviews Genetics 3: 737. Other RNA antagonists such as RNAi-induced silencing complexes with a discontinuous passenger strand have also been reported (Leuschner, et al. (2006) EMBO Reports 7:314).
It would be desirable to have antagonists that block or inhibit activity of a mammalian complement component 6 (C6) protein, for example. It would be further desirable to have antagonists that can be used to prevent, treat, or reduce the severity of neuropathies that are known or suspected of being associated with formation of the MAC.